NF-kB control of neuronal apoptosis in Alzheimer disease

在2011财年，我们实现了以下目标： 1. 完成了COX 2抑制剂调节细胞死亡和炎症机制的研究。 我们的观察结果表明，塞来昔布通过COX 2依赖性途径加重活化的CD 4 + T细胞母细胞的凋亡。 相反，塞来昔布通过COX 2非依赖性途径抑制促炎性TNF超家族受体和配体的表达。 塞来昔B的抗炎作用通过抑制NF-B家族成员Rel介导。 因此，Rel缺陷型CD 4 + T细胞母细胞在许多方面类似于塞来昔布处理的母细胞。 2. 我们进一步扩展了上述塞来昔布研究，以测试另外四种COX 2抑制剂。 这些抑制剂中的两种影响细胞死亡并干扰Rel诱导，如塞来昔布所述，而另外两种对Rel诱导或TNF超家族受体和配体的表达没有影响。 这些观察结果表明，昔布类抗炎作用的主要机制是通过抑制Rel。

During fiscal year 2011, we accomplished the following: 1. Completed studies on the mechanism of COX2 inhibitors in regulating cell death and inflammation. Our observations demonstrate that celecoxib accentuates apoptosis of activated CD4+ T cell blasts via a COX2-dependent pathway. In contrast, celecoxib inhibits expression pro-inflammatory TNF super-family receptors and ligands via a COX2-independent pathway. The anti-inflammatory effects of celecoxib are mediated via suppression of the NF-κB family member, Rel. Accordingly, Rel-deficient CD4+ T cell blasts resemble celecoxib-treated blasts in many respects. 2. We further extended the celecoxib studies described above to test four additional COX2 inhibitors. Two of these inhibitors affected cell death and interfered with Rel induction as noted for celecoxib, whereas the other two had no effect on Rel-induction or expression of TNF superfamily receptors and ligands. These observations indicate that a major mechanism of anti-inflmmatory effects of coxibs is via suppression of Rel.